Alix and ALG-2 are involved in tumor necrosis factor receptor 1-induced cell death.
Alix/AIP1 regulates cell death in a way involving interactions with the calcium-binding protein ALG-2 and with proteins of ESCRT (endosomal sorting complex required for transport). Using mass spectrometry we identified caspase-8 among proteins co-immunoprecipitating with Alix in dying neurons. We next demonstrated that Alix and ALG-2 interact with pro-caspase-8 and that Alix forms a complex with the TNFalpha receptor-1 (TNF-R1), depending on its capacity to bind ESCRT proteins. Thus, Alix and ALG-2 may allow the recruitment of pro-caspase-8 onto endosomes containing TNF-R1, a step thought to be necessary for activation of the apical caspase. In line with this, expression of Alix deleted of its ALG-2-binding site (AlixDeltaALG-2) significantly reduced TNF-R1-induced cell death, without affecting endocytosis of the receptor. In a more physiological setting, we found that programmed cell death of motoneurons, which can be inhibited by AlixDeltaALG-2, is regulated by TNF-R1. Taken together, these results highlight Alix and ALG-2 as new actors of the TNF-R1 pathway.
Mahul-Mellier
Anne-Laure
AL
INSERM, U836, Equipe 2, Neurodégénérescence et Plasticité, Grenoble F-38042, France.
Strappazzon
Flavie
F
Petiot
Anne
A
Chatellard-Causse
Christine
C
Torch
Sakina
S
Blot
Béatrice
B
Freeman
Kimberley
K
Kuhn
Loriane
L
Garin
Jérome
J
Verna
Jean-Marc
JM
Fraboulet
Sandrine
S
Sadoul
Rémy
R
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D002642:Chick Embryo; D004705:Endocytosis; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D009432:Neural Crest / Q000196:embryology; D009474:Neurons / Q000378:metabolism; D017434:Protein Structure, Tertiary; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C097753:PDCD6 protein, human; C117020:PDCD6IP protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D053181:Caspase 8